Palivizumab passive immunisation against respiratory syncytial virus (RSV) in at-risk pre-term infants - NHS England
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COVID-19 rapid policy statement
Palivizumab passive immunisation against
respiratory syncytial virus (RSV) in at-risk
pre-term infants
Introduction
In response to the public health emergency posed by coronavirus disease 2019 (COVID-19),
NHS England and NHS Improvement, working with the Devolved Administrations (DAs), has
established a rapid policy development process to aid clinicians in offering best care and
advice to patients with, or at risk of, COVID-19 across the UK. This document sets out the
interim clinical commissioning position for passive immunisation with palivizumab against
respiratory syncytial virus (RSV) in at-risk pre-term infants.
Commissioning position
The proposal is: to extend passive immunisation against RSV with palivizumab in at-risk pre-
term infants in accordance with the criteria set out in this document.
Equality statement
Promoting equality and addressing health inequalities are at the heart of the four nations’
values. Throughout the development of the policies and processes cited in this document,
we have:
• given due regard to the need to eliminate discrimination, harassment and
victimisation, to advance equality of opportunity, and to foster good relations between
people who share a relevant protected characteristic (as cited under the Equality Act
2010 or equivalent equality legislation) and those who do not share it; and
• given regard to the need to reduce inequalities between patients in access to and
outcomes from healthcare services and to ensure services are provided in an
integrated way where this might reduce health inequalities.
Plain language summary
In the UK, respiratory syncytial virus (RSV) is a seasonal winter virus causing lower
respiratory tract infections (LRTIs) from October to March. Most RSV infections occur in a
relatively short epidemic of about six weeks. LRTI, resulting from RSV, usually causes mild,self-limiting illness, but may cause severe illness in vulnerable infants at high risk of LRTI
resulting in hospitalisation.
Palivizumab (administered as an intramuscular injection) is used to provide protection
against RSV in at-risk patients, and has been shown to decrease hospitalisation in this
group. It is currently part of a UK-wide immunisation schedule as per guidance issued by
Joint Committee on Vaccination and Immunisation (JCVI) in 2010, which recommends its
use in premature infants with conditions affecting the lungs and/or heart, and children with
impaired immune systems.
This policy statement proposes the extension of the eligibility criteria for immunisation with
palivizumab for this year only (within the context of the current COVID-19 pandemic) to a
further group of at-risk infants as set out in this policy. The proposed extension for
palivizumab immunisation is outlined in text on page 4 and pictorially as an algorithm in
Appendix 1.
Overview
The condition
RSV infection manifests predominantly as a respiratory illness and is responsible for 75-80%
of all LRTI cases in young children (Green CA, 2016). It is one of the leading causes of
hospitalisation in the first year of life. Previous infection with RSV may only confer partial
immunity and so individuals may be repeatedly infected with the same or different strains of
RSV.
In most cases, the infection is mild and self-limiting, but severe illness may occur in
vulnerable infants, resulting in hospitalisation and/or admission to intensive care. Babies at
highest risk of serious RSV illness are pre-term infants with conditions that predispose them
to complications from RSV infection such as chronic lung disease (CLD – also known as
bronchopulmonary dysplasia [BPD]), congenital heart disease (CHD), multiple congenital
anomalies and immunodeficiencies.
Intervention
Palivizumab is a recombinant humanised monoclonal antibody directed against the F-protein
on the surface of the RSV. It is a form of passive immunisation, not a vaccine, and as such
only provides short-term protection against RSV. Up to five intramuscular doses (of
15mg/kg) at monthly intervals should be administered over the RSV season.1 Commonly
occurring adverse events or side effects include injection site reactions, fever, and diarrhoea.
Current Treatment
The JCVI guidance in the UK currently recommends the use of palivizumab prophylaxis to
protect at-risk infants in whom RSV infection is likely to cause serious illness or death (JCVI,
2010). Palivizumab prophylaxis in the UK is currently recommended for use in children in the
age groups displayed in Table 1 AND meeting any of the clinical criteria below the table (the
relevance of the shaded areas is explained further in the text below the table):
1
Defined as the beginning of calendar week 40 (ie the beginning of October) to the end of calendar week 8 (ie
the end of February) the following year
2 | Palivizumab passive immunisation against respiratory syncytial virus in at-risk pre-term infantsTable 1: Cost-effective us of palivizumab. Reproduced from the JCVI statement on RSV
immunisation, 2010
Gestational age at birth (weeks)
Chronological ≤24+0 24+1 to 26+1 to 28+1 to 30+1 to 32+1 to
age (months) 26+0 28+0 30+0 32+0 34+0intervention for the prevention of RSV infection and there are no alternative interventions at
present.
Proposed Treatment
In light of the present COVID-19 pandemic, it has been proposed that these criteria be
widened to include a larger population of at-risk infants to decrease hospitalisation and
intensive care admission rates with the aim of reducing the risk of nosocomial infection and
pressure on the health system this winter. This would include at-risk pre-term infants5 with
CLD or BPD in their first year of life (Sommer C, 2014).
Evidence summary
An evidence review of three academic publications on the use of palivizumab immunisation
against RSV in at-risk infants was conducted by Solutions for Public Health (SPH). The
evidence of effectiveness of palivizumab in infants with co-morbidities is well recognised.
The evidence review by SPH suggested some benefit with palivizumab passive
immunisation in preventing RSV hospital admissions in infants born pre-term with and
without co-morbidities such as BPD. The summary of the evidence from the three papers is
in Appendix 2.
Implementation (extended use of palivizumab)
Eligibility criteria
Infants who meet the current JCVI recommendations will continue to be eligible for
palivizumab. In addition, during the COVID-19 pandemic, the following additional access
criteria are permitted:
• Infants born at ≤34+0 weeks gestation; AND
• Diagnosed with CLD6; AND
• Discharged from hospital on home oxygen on or after 1 January 2020.
Dose
The recommended dose of palivizumab is 15mg/kg of body weight, given once a month.
Where possible the first dose should be administered at the start of the RSV season.
Subsequent doses should be administered monthly throughout the RSV season for up to a
maximum of five doses. Where the course of treatment begins later in the RSV season then
up to five doses should be given one month apart until the end of the RSV season.
Contraindications and precautions
Palivizumab should not be given to infants or children who have had:
• a confirmed anaphylactic reaction to a previous dose of palivizumab
5
Defined as being born at ≤34 weeks gestational age
6
Defined for the purpose of this policy as “preterm infants with compatible x-ray changes who continue to
receive supplemental oxygen or respiratory support at 36 weeks post-menstrual age” (Department of Health,
2015). Please note that the JCVI define CLD as “oxygen dependency for at least 28 days from birth” (JCVI,
2010).
4 | Palivizumab passive immunisation against respiratory syncytial virus in at-risk pre-term infants• a confirmed anaphylactic reaction to any components of palivizumab
• a confirmed anaphylactic reaction to another humanised monoclonal antibody.
Palivizumab should be given with caution to patients with thrombocytopenia or any
coagulation disorder.
A mild febrile illness, such as mild upper respiratory tract infection, is not usually reason to
defer administration of palivizumab. A moderate to severe acute infection or febrile illness
may warrant delaying the use of palivizumab unless, in the opinion of the physician,
withholding palivizumab entails a greater risk.
Safety reporting
Any suspected adverse drug reactions (ADRs) for patients receiving palivizumab should be
reported directly to the Medical and Healthcare products Regulatory Agency (MHRA) using
the Yellow Card reporting scheme at https://yellowcard.mhra.gov.uk/.
Governance
Data collection requirement
Provider organisations in England should register all patients using prior approval software
(alternative arrangements in Scotland, Wales and Northern Ireland will be communicated)
and ensure monitoring arrangements are in place to demonstrate compliance against the
criteria as outlined.
Effective from
This policy will be in effect from the date of publication.
Policy review date
This is an interim rapid clinical policy statement, which means that the full process of policy
production has been abridged: public consultation has not been undertaken. This policy
pertains to the COVID-19 pandemic and the RSV season (2020/21) and will be reviewed on
31 March 2021.
Definitions
A form of lung disease found in infants that were born prematurely due to
Bronchopulmonary
incomplete development of the lungs and airways. Its defining criterion is the
dysplasia (BPD)
requirement for respiratory support at 36 weeks gestational age.
Chronic lung Also known as chronic lung disease of prematurity or chronic neonatal lung
disease (CLD) disease and is used interchangeably with BPD.
Respiratory An enveloped RNA pneumovirus that is a common cause of respiratory tract
syncytial virus infection.
(RSV)
5 | Palivizumab passive immunisation against respiratory syncytial virus in at-risk pre-term infantsReferences
1. Department of Health (2015). Chapter 27a, Respiratory Syncytial Virus. Immunisation
against infectious disease (Green Book). London: Department of Health.
Available from:
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachm
ent_data/file/458469/Green_Book_Chapter_27a_v2_0W.PDF
2. Green CA, Yeates D, Goldacre A, et al. Admission to hospital for bronchiolitis in
England: trends over five decades, geographical variation and association with
perinatal characteristics and subsequent asthma. Arch Dis Child. 2016;101(2):140-
146.
Available from: https://pubmed.ncbi.nlm.nih.gov/26342094/
3. Jardine E, Wallis C. Core guidelines for the discharge home of the child on long term
assisted ventilation in the United Kingdom.Thorax 1998;53:762-767.
Available from: https://thorax.bmj.com/content/thoraxjnl/53/9/762.full.pdf
4. Joint Committee on Vaccination and Immunisation Statement on immunisation for
Respiratory Syncytial Virus, 2010.
Available from:
https://webarchive.nationalarchives.gov.uk/20120907151316/http://www.dh.gov.uk/pr
od_consum_dh/groups/dh_digitalassets/@dh/@ab/documents/digitalasset/dh_12039
5.pdf
5. Luna MS, Manzoni P, Paes B, et al. Expert consensus on palivizumab use for
respiratory syncytial virus in developed countries. Paediatr Respir Rev. 2020;33:35-
44.
Available from: https://pubmed.ncbi.nlm.nih.gov/31060948/
6. Rogovik AL, Carleton B, Solimano A, Goldman RD. Palivizumab for the prevention of
respiratory syncytial virus infection. Can Fam Physician. 2010;56(8):769-772.
Available from: https://pubmed.ncbi.nlm.nih.gov/20705882/
7. Sommer C, Resch B, Simões EA. Risk factors for severe respiratory syncytial virus
lower respiratory tract infection. Open Microbiol J. 2011;5:144-154.
Available from: https://pubmed.ncbi.nlm.nih.gov/22262987/
6 | Palivizumab passive immunisation against respiratory syncytial virus in at-risk pre-term infantsAppendix 1
Algorithm for immunisation with palivizumab under the extended access criteria
Does the infant meet the
current JCVI criteria for YES Proceed to immunisation
immunisation with with palivizumab
palivizumab?*
NO
Was the infant born at ≤34+0 NO
weeks gestation?
YES
Does the infant have a NO Not eligible for immunisation
diagnosis of chronic lung
with palivizumab
disease?**
YES
NO
Was the infant discharged
on home oxygen on or after
1 January 2020?
YES
Eligible for immunisation
under the extended criteria
of this policy
* See p2-3 of this document for current JCVI criteria
** Defined for the purpose of this policy as “preterm infants with compatible x-ray changes who
continue to receive supplemental oxygen or respiratory support at 36 weeks post-menstrual age”
(Department of Health, 2015). Please note that the JCVI define CLD as “oxygen dependency for at
least 28 days from birth” (JCVI, 2010).
7 | Palivizumab passive immunisation against respiratory syncytial virus in at-risk pre-term infantsAppendix 2: Extending palivizumab immunisation for
respiratory syncytial virus in at-risk groups of infants to
prevent hospitalisation during the winter season
Narrative summary of papers presented for review
Three papers were presented for review by NHS England:
• Paper 1, the IMpact-RSV trial, is a randomised controlled trial conducted in 139
centres in the US, UK and Canada, including 1,502 children; of whom 740 were
premature but did not have bronchopulmonary dysplasia (BPD).
• Paper 2 is a prospective single-arm multicentre study in 18 hospitals in Canada,
evaluating 444 children who received palivizumab; of whom 324 were premature and
did not have BPD.
• Paper 3 is a prospective observational study in 12 hospitals in Burgundy, France,
evaluating palivizumab for premature infants without BPD in two RSV seasons,
compared to three previous seasons when it was not used.
Paper 1: IMpact-RSV Study Group 1998. Palivizumab, a humanized respiratory
syncytial virus monoclonal antibody, reduces hospitalization from respiratory
syncytial virus infection in high-risk infants
This paper reports a randomised double-blind placebo-controlled trial conducted in 119
centres in the US, 11 in the UK and nine in Canada during the 1996 to 1997 RSV season.
The study included children who were either ≤35 weeks gestation and ≤6 months old, or
were ≤24 months old with a diagnosis of BPD requiring ongoing treatment. Exclusion criteria
included hospitalisation at entry anticipated to last >30 days, mechanical ventilation at entry,
life expectancyFollow-up was for 150 days from randomisation (including at each visit, each hospital day 7
and 30 days after the last scheduled injection). Of the whole study population, 99%
completed follow-up; 94% of placebo and 92% of the palivizumab group received all five
injections; more than 95% in both groups received at least four injections; the proportions
receiving none, one, two and three injections were similar in both groups. These data were
not reported separately for the groups that did and did not have BPD.
Paper 2: Oh et al 2002. Palivizumab prophylaxis for respiratory syncytial virus in
Canada: utilization and outcomes
This paper reports a prospective single-arm multicentre study in 18 sites in six provinces of
Canada that aimed to provide insight into the use of palivizumab in practice. Children were
eligible if they 1) were enrolled through the 1999/2000 Canadian Therapeutic Products
Programmes’ Special Access Programme, born at ≤32 weeks gestation and(defined as oxygen dependence on day 28 of extra-uterine life) in the 2002 to 2003 and 2003
to 2004 RSV seasons where birth date was between 15 April and 31 January and the child
wasrequiring hospitalisation was 2.4%.9 Compared with children who were not hospitalised for
RSV-positive LRTIs (n=435), children hospitalised for RSV-positive LRTIs (n=9) were
significantly more likely to have BPD (55.6% vs 20.7%, p=0.03), and more likely (non-
significant differences) to have siblings (66.6% vs 46.6%, p=0.14), to be non-Caucasian
(33.3% vs 15.1%, p=0.14), to have received mechanical ventilation as a neonate (88.9% vs
67.6%, p=0.18) and to reside in smoking households (44.4% vs 21.7%, p=0.19). Two
children were hospitalised for RTIs more than once, all their five hospitalisations being in
April or May after their last injection.
Oh et al 2002 reported that, among premature (≤32 weeks gestation) children without BPD
(data available for 324 of 345 children), nine children were hospitalised for RTIs. Among
these nine, eight had LRTIs of which four were RSV-positive and two were RSV negative.
The incidence of RSV-positive LRTIs requiring hospitalisation in this group was 1.6%.
Oh et al 2002 reported that, among the children with BPD (data available for 35 of 40
children), eight were hospitalised for RTIs. All eight had LRTIs of which one was RSV-
positive and six were RSV negative. The incidence of RSV-positive LRTIs requiring
hospitalisation in this group was 3.3%.
Oh et al 2002 reported that, among the premature (≤32 weeks gestation) children who also
had BPD (data available for 60 of 68 children), nine were hospitalised for RTIs. Among these
nine, eight had LRTIs of which four were RSV-positive and three were RSV negative. The
incidence of RSV-positive LRTIs requiring hospitalisation in this group was 7.6%.
Oh et al 2002 reported that, among the children who received palivizumab for another
reason (data available for 25 of 27 children), one was hospitalised for a RTI, which was a
RSV-negative LRTI; the incidence of RSV-positive LRTIs in this group was 0%.
Grimaldi et al 2007 obtained data for all children in their study cohort who were hospitalised
with RSV bronchiolitis10 at any of the 12 hospitals in the Burgundy region which accepted
children during the five RSV seasons from 1 December to 30 April between 1999 and 2004.
All children hospitalised for bronchiolitis were screened for RSV.
The authors reported that for children ≤30 weeks gestation without BPD (their study cohort),
the RSV bronchiolitis hospitalisation rate was significantly lower in the two seasons with
palivizumab prophylaxis compared to the previous three seasons where it was not
administered: 1.1% vs 13.5%, pThe child with an RSV bronchiolitis hospitalisation in the palivizumab group had received
three palivizumab treatments prior to hospitalisation. The number needed to treat in order to
prevent one RSV bronchiolitis hospitalisation was 6 (95% CI 4 to 11).
Total days of RSV hospitalisation
The IMpact-RSV trial 1998 reported, for the whole trial population, significantly fewer days
(per 100 children) of RSV hospitalisation in the palivizumab group (36.4 days for the
palivizumab group vs 62.6 days for the placebo group, pHospitalisation for any reason
The IMpact-RSV trial reported, for the whole trial population, significant differences in
incidence of all hospitalisations (24% for palivizumab recipients vs 31% for the placebo
group, p=0.011) and total days in hospital per 100 children (191 vs 242 days respectively,
p=0.005).
Respiratory hospitalisation
The IMpact-RSV trial 1998 reported, for the whole trial population, significant differences in
incidence of all respiratory hospitalisation (16% for palivizumab recipients vs 22% for the
placebo group, p=0.008) and total days of respiratory hospitalisation per 100 children (124
vs 180 days respectively, p=0.004).
Respiratory hospitalisation unrelated to RSV
The IMpact-RSV trial 1998 reported, for the whole trial population, no significant differences
in incidence of respiratory hospitalisations unrelated to RSV (13% for palivizumab recipients
vs 14% for the placebo group, p=0.470) and total days per 100 children (88 vs 118 days
respectively, p=0.369).
Oh et al 2002 reported that, for the trial as a whole (444 evaluable subjects), there were ten
hospitalisations for respiratory events that were deemed unlikely to be RSV-related RTIs by
the treating physician (three were tested for RSV and were negative).
Respiratory events managed as outpatients
Oh et al 2002 reported that, for the whole trial population (444 evaluable subjects), there
were 99 respiratory events that were managed as outpatients (70 patients, 57 with a single
event). 86 of these respiratory events were confirmed RTIs, the majority being managed in
either the physician’s office (43%) or the emergency room (36%). These included 26 LRTIs
(24 patients, five tested for RSV and all five were positive) and 60 upper RTIs (49 patients).
For the other 13 respiratory events, the physician indicated to the parent/caregiver that they
were unlikely to be RSV related.
Otitis media
The IMpact-RSV trial 1998 reported, for the whole trial population, no significant difference in
the proportion of children with at least one episode of otitis media (42% in palivizumab
recipients vs 40% in the placebo group, p=0.505).
Safety
Adverse events related to the treatment
The IMpact-RSV trial 1998 reported adverse events for the whole trial group only (n=1,502)
and not separately for those who were premature and did or did not have BPD. They
reported adverse events judged by the blinded investigator to be related to the study
treatment for 11% of the palivizumab group and 10% of the placebo group. No statistically
significant differences were reported in relation to events by body system (Table 2).
13 | Palivizumab passive immunisation against respiratory syncytial virus in at-risk pre-term infantsDiscontinuation of injections because of adverse events was rare (0.3%). 2.7% of the
palivizumab group and 1.8% of the placebo group reported adverse events related to the
injection site16 including erythema (1.4% vs 1.2%), pain (0.6% vs 0.0%), induration/swelling
(0.6% vs 0.2%), and bruising (0.3% vs 0.4%). These were generally mild and of short
duration; none were serious.
There were mild or moderate elevations of aspartate aminotransferase (AST) in 3.6% of the
palivizumab group and 1.6% of the placebo group, with corresponding figures for alanine
aminotransferase (ALT) being 2.3% and 2.0%.11 Elevations of creatinine, blood urea nitrogen
and renal adverse events were infrequent and at a similar rate in both groups.
Table 2: Most frequently reported adverse events that were judged by the blinded
investigator as potentially related to the study drug (IMpact-RSV trial 1998)
Palivizumab Placebo p value
Fever 2.8% 3.0% 0.870
Nervousness 2.5% 2.6% 0.865
Injection site reaction17 2.3% 1.6% 0.444
Diarrhoea 1.0% 0.4% 0.357
Rash 0.9% 0.2% 0.179
Upper respiratory tract illness 0.3% 0.4% 1.000
Aspartate aminotransferase (AST) increased 12 0.5% 0.6% 0.726
Alanine aminotransferase (ALT) increased 12 0.3% 0.4% 0.670
Liver function abnormal (primarily elevations of
both AST and ALT) 0.3% 0.2% 1.000
Vomiting 0.3% 0.4% 0.670
Cough 0.3% 0.2% 1.000
Oh et al 2002 reported that palivizumab was discontinued for two children because of
perceived side effects based on parent or caregiver reports. No further details were
provided.
16
These figures are taken from the narrative in the paper and differ from those reported in Table 3 in the paper.
Table 3 reported lower percentages with an injection site reaction and with elevated AST or ALT than reported
in the narrative. The reason for this was not clear.
17
These results are taken from Table 3 in the paper and differ from those reported in the narrative. Table 3
reported lower percentages with an injection site reaction and with elevated AST or ALT than reported in the
narrative. The reason for this was not clear.
14 | Palivizumab passive immunisation against respiratory syncytial virus in at-risk pre-term infantsGrimaldi et al 2007 did not specifically report adverse events. However, among the reasons
reported for why some in the palivizumab group were not given palivizumab, none were
reported to have had it discontinued because of side effects related to previous doses.
Deaths
The IMpact-RSV trial 1998 reported four deaths (0.4%) in the palivizumab group and five
deaths (1.0%) in the placebo group during the trial, two and zero respectively occurred
during hospitalisation for RSV, but no death was judged to be related to palivizumab.
Immunogenicity
The IMpact-RSV trial 1998 measured anti-palivizumab binding at intervals during the study.
Titres greater that 1:40 were found in 1.2% of the palivizumab group and 2.8% of the
placebo group, but they were generally single elevations and not associated with a pattern of
adverse events or low palivizumab concentrations.
References
• Grimaldi M, Gouyon B, Sagot P, et al. Palivizumab efficacy in preterm infants with
gestational age ≤30 weeks without bronchopulmonary dysplasia. Pediatr Pulmonol.
2007;42(3):189-192. doi:10.1002/ppul.20503
Available from https://pubmed.ncbi.nlm.nih.gov/17243184/
• Oh PI, Lanctôt KL, Yoon A, et al. Palivizumab prophylaxis for respiratory syncytial virus in
Canada: utilization and outcomes. Pediatr Infect Dis J. 2002;21(6):512-518.
doi:10.1097/00006454-200206000-00007
Available from https://pubmed.ncbi.nlm.nih.gov/12182374/
• The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus
monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in
high-risk infants. Pediatrics 1998; 102(3 Pt 1): 531-7.
Available from https://pubmed.ncbi.nlm.nih.gov/9738173/
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